Estrogen-based hormone therapy has had its ups and downs. In 2002, one arm of the Women's Health Initiative, a large-scale longitudinal trial of women examining hormone therapy, was halted due to an unexpected increase in adverse cardiovascular events among women on the therapy. The ensuing publicity resulted in many women ditching their regimens. But subsequent research (see for example this study, and this one) has shown that women who start treatment at menopause or soon afterward can benefit.

Now, a new study conducted by researchers based at Stanford and the University of California-San Francisco suggests that for women who are carriers of a well-known genetic risk factor for cognitive decline in general and Alzheimer's disease in particular, beginning an estrogen regimen at menopause may be a good idea.

As I wrote in my news release about the study, which was just published in the open-access online journal PLOS ONE and led by Stanford psychopharmacologist Natalie Rasgon, MD, PhD:

All people carry two copies of a gene called ApoE. (One copy is inherited from each parent). Like genes for eye or hair color, ApoE comes in more than one version. Some 15 to 20 percent of Americans carry at least one copy of ApoE4, a version that puts them at substantially increased risk for late-onset Alzheimer’s disease in comparison with people who are not ApoE4 carriers.

For their work, the researchers recruited 70 healthy, high-functioning middle-aged women who had all been on hormone therapy since menopause and divided them into two groups: One group stayed on their regimen, the others dropped it.

An analysis of blood samples drawn from the volunteers when they first started on the study and again two years later showed significant differences between the two groups. In those women with one or more copies of ApoE4, a molecular measure of cellular aging called telomere shortening was greatly accelerated compared with its speed in women not carrying ApoE4. In other words, the cells of women carrying ApoE4 seemed to be aging at a faster rate than was seen in the cells of non-carriers.

Interestingly, though, carriers who stayed on the regimen throughout the two-year duration of the study showed no such signs of accelerated biological aging.

“Our take-home findings from this study were, first, that ApoE4 carriers are at greater risk of biological aging, which is associated with negative health outcomes and, second, that if you were a postmenopausal ApoE4 carrier, being on estrogen therapy was a good thing for telomere length, an established measure of biological aging at the cellular level,” Rasgon told me during an interview. “This brings us a step closer to being able to identify which women will benefit the most from estrogen replacement therapy.”

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The scenario many of us learned in school is that two X chromosomes make someone female, and an X and a Y chromosome make someone male. These are simplistic ways of thinking about what is scientifically very complex.